Comparative genomic analyses have been instrumental for the study of a wide range of hereditary and infectious diseases and physical traits. However, to fully interpret the results of these studies and to take full advantage of the large amounts of genomic data that is being generated by next-generation sequencing methods, it is necessary to interpret the results in the context of population and evolutionary history. This involves not only a more precise description of the phylogenetic relationships among species, but also an assessment of the uniqueness among populations. We recently completed a long ongoing study of the remnant Florida panther project (Puma concolor coryi) in southern Florida. In 1995, conservation managers translocated eight female pumas (P. c. stanleyana) from Texas to increase depleted genetic diversity, improve population numbers and reverse indications of inbreeding depression. We assessed the demographic, population-genetic and biomedical consequences of this restoration experiment and showed that panther numbers increased three-fold, genetic heterozygosity doubled, survival and fitness measures improved and inbreeding correlates declined significantly. Our comparative genomic studies have included many of the members of the Felid family but have recently also included other carnivores and vertebrate species. The number of available species for genomic comparisons is rapidly increasing, and we have been actively collaborating with researchers at the Broad Institute, Washington University Sequencing Center, and Shenzhen-BGI in developing, annotating, and interpreting whole genome resources, in conjunction with the G10K community of scientists who are helping coordinate access to samples and analyze the data. These data will inform comparative studies of gene function and genomic organization, and will provide additional resources for population genetic studies.